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New optimism for patients with cancer

New optimism for patients with cancer . As cancer therapy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients Bortezomib and tipifarnib are two new targeted treatments for hematologic malignancies . Bortezomib.

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New optimism for patients with cancer

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  1. New optimism for patients with cancer • As cancer therapy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients • Bortezomib and tipifarnib are two new targeted treatments for hematologic malignancies

  2. Bortezomib • A proteasome inhibitor • Has shown good efficacy as a single agent and in combination in patients • with relapsed multiple myeloma • as initial treatment, including prior to autologous stem cell transplantation • Has been studied as monotherapy and in combination with standard treatments, such as dexamethasone, chemotherapy, and with newer agents such as the IMiDs, thalidomide and lenalidomide • Is well-tolerated, including in combination

  3. Clinical course of multiple myeloma Survival (years) 0 1 2 3 4 5 Diagnosis to death 3–4 years • Relapsed disease • Transient response to therapy 1–2 years • Relapsed and refractory • Resistant to all therapy • Universally fatal 6–9 months

  4. b2 b1 Post- glutamylsite Trypticsite H b7 b3 N N H Bortezomib b6 b4 Chymo- trypticsite b5 O OH N B OH O N Bortezomib: a potent first-in-class proteasome inhibitor Dipeptidyl boronic acidderivative Cross-section of b-ring (reversible inhibitor of chymotryptic active site of proteasome  subunit) Janssen-Cilag 2003

  5. X X X Bortezomib

  6. Summary of bortezomib data in relapsed/refractory MM 1. Abstracts in Blood 2005;106 (ASH 2005) 2. Blood 2005;105:3058–65

  7. CR+PR 34% CR+PR 45% n is shown by the number on each bar Response to bortezomib by prognostic factor and line of treatment >1 prior treatment and MM refractory to prior treatment resulted in lower responses to bortezomib Richardson et al. ASCO 2005; Sonneveld et al. IMW 10, Sydney, 2005

  8. Bortezomib: higher response rates in second-line therapy than later therapy CR nCR PR 100 P=0.0035 80 P<0.0001 60 45 Proportion of patients (%) 40 34 26 32 20 13 21 0.5 nCR 23 6 7 13 0 6 2 6 Bortezomib Dex Bortezomib Dex 1 prior line of therapy >1 prior line of therapy Sonneveld et al. IMW 10, Sydney, 2005

  9. Single-agent bortezomib active in newly diagnosed MM • Well tolerated: safety profile similar to previous studies • Neuropathy frequently prevalent at baseline *Stem cells successfully harvested from 13 patients: 12 received transplants Richardson et al. Blood 2004;104:100a (abstract 336)Jagannath et al. Haematologica 2005;90(Suppl 1):148 (abstract P0.725)

  10. Bortezomib + dexamethasone in newly diagnosed MM Data available for 46/52 patients • Stem cell collection adequate for all patients (median CD34+ cells 6.7 x 106/kg; range 2–33); median 2 collections required (range 1–4) • Well tolerated: AEs mainly grade 1/2 • PN: 6% grade 3, 8% grade 2 • 1 grade 4 GI • Results form basis for IFM Phase III trial of bortezomib + Dex vs VAD Harousseau et al. Haematologica 2005;90(Suppl 1):148(abstract P0.724)

  11. Bortezomib combination protocols in previously untreated patients *VEL: Bortezomib – VELCADE® 1. Abstracts in Blood 2005;106 (ASH 2005) 2. Abstract in Blood 2004;104 (ASH 2004)

  12. 72% 85% 64% 70% 70% 60% 60% 45% 50% 50% 28% 40% 40% 24% 30% 30% 11% 13% 20% 20% 6% 6% 2% 10% 10% 0% 0% CR IF- CRIF+ PR MR SD CR IF- CR IF+ PR SD MPV response rates (n=53)Analysis of best response achieved so far 1st cycle MPV Best response: median 3 cycles Mateos et al. Blood 2005;106 (Abs 786) ASH 2005

  13. Adverse events from APEX (all patients) †Deaths within 30 days after last dose *69% of 310 patients on bortezomib reported symptoms of PN at baseline ** SUMMIT/CREST: PN ≥ grade 3, 13% Thrombocytopenia ≥ grade 3, 30% Richardson et al.N Engl J Med 2005;352:2487–98

  14. Tipifarnib • A specific inhibitor of farnesyltransferase • Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib, even in patients with poor prognosis and elderly, poor-risk patients

  15. Oral formulation Potent and selective inhibitor of farnesylation Key enzyme involved in multiple tumor-promoting pathways Essential for the functioning of signal transduction cascades associated with cell proliferation Potent inhibitor of malignant cell line proliferation Cl Cl N H 2 N N O N Tipifarnib:targeted farnesyltransferase inhibitor

  16. Key enzyme in many pathways Farnesylated proteins Ras (H-, K-, N-) Rho (B,E) Lamins (A, B) Centromere-binding proteins Farnesyltransferase Blocking FTase has therapeutic potential

  17. Phase II trial of tipifarnib: efficacy Response confirmed 28 days after initial response Relapsed Refractory Total (n=135) (n=117) (n=252) CR 7 (5%) 4 (3%) 11 (4%) Confirmed CR 2 (1%) 1 (1%)  3 (1%) SD (>8 weeks) 8 (6%) 5 (4%) 13 (5%) Total 15 (11%) 9 (8%) 24 (10%) Harousseau et al. Presentedat ASH 2003

  18. Targeted therapy • Is among the most exciting new development in cancer treatment • Specifically attacks the malignancy for improved efficacy and overall safety • Underscores an important shift in the treatment paradigm for multiple myeloma and other hematologic malignancies – a shift from empirical chemotherapeutic regimens with significant side effects towards rational, targeted, effective therapies with improved tolerability

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